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Low TLR9 expression defines an aggressive subtype of triple-negative breast cancer

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Abstract

Toll-like receptor-9 (TLR9) is a DNA receptor widely expressed in cancers. Although synthetic TLR9 ligands induce cancer cell invasion in vitro, the role of TLR9 in cancer pathophysiology is unclear. We discovered that low tumor TLR9 expression is associated with significantly shortened disease-specific survival in patients with triple negative but not with ER+ breast cancers. A likely mechanism of this clinical finding involves differential responses to hypoxia. Our pre-clinical studies indicate that while TLR9 expression is hypoxia-regulated, low TLR9 expression has different effects on triple negative and ER+ breast cancer invasion in hypoxia. Hypoxia-induced invasion is augmented by TLR9 siRNA in triple negative, but not in ER+ breast cancer cells. This is possibly due to differential TLR9-regulated TIMP-3 expression, which remains detectable in ER+ cells but disappears from triple-negative TLR9 siRNA cells in hypoxia. Our results demonstrate a novel role for this innate immunity receptor in cancer biology and suggest that TLR9 expression may be a novel marker for triple-negative breast cancer patients who are at a high risk of relapse. Furthermore, these results suggest that interventions or events, which induce hypoxia or down-regulate TLR9 expression in triple-negative breast cancer cells may actually induce their spread.

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Acknowledgments

This work was funded by grants from the Lapland Cultural Foundation (K.S.V., A.J-V., K.S.S.), Northern Finnish Duodecim Foundation (A.J-V), the Finnish Medical Foundation (P.K.), Oulu University Scholarship Foundation (J.H.K.), Cancer Foundation of Northern Finland (J.H.K.), Elsa U. Pardee Foundation (K.S.S) and Department of Defense (K.S.S., D.G.).

Conflict of interest

The authors declare no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Medicine, Division of Hematology-Oncology, University of Alabama at Birmingham, SHEL 514, 1825 University Blvd, Birmingham, AL, 35294-3300, USA

    Johanna Tuomela, Jouko Sandholm, Joanna Ilvesaro, Dongquan Chen, Christine Pressey, Kevin W. Harris & Katri S. Selander

  2. Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA

    Johanna Tuomela, Jouko Sandholm, Joanna Ilvesaro, Dongquan Chen, Christine Pressey, Kevin W. Harris, David Graves & Katri S. Selander

  3. Department of Oncology and Radiotherapy, Oulu University Hospital, Oulu, Finland

    Peeter Karihtala & Arja Jukkola-Vuorinen

  4. Department of Pathology, Lapland Central Hospital, Rovaniemi, Finland

    Katri S. Vuopala

  5. Department of Pathology, Oulu University Hospital, Oulu, Finland

    Joonas H. Kauppila & Saila Kauppila

  6. Department of Surgery, Oulu University Hospital, Oulu, Finland

    Joonas H. Kauppila

  7. Department of Anatomy & Cell Biology, University of Oulu, Oulu, Finland

    Joonas H. Kauppila

  8. Department of Cell Biology and Anatomy, University of Turku, Turku, Finland

    Pirkko Härkönen

  9. Birmingham Veterans Affairs Medical Center, Birmingham, AL, USA

    Kevin W. Harris

  10. Department of Chemistry, University of Alabama at Birmingham, Birmingham, AL, USA

    David Graves

  11. Department of Oncology, Cancer Center of Eastern Finland, Kuopio University Hospital, Kuopio, Finland

    Päivi K. Auvinen

  12. Department of Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland

    Ylermi Soini

Authors
  1. Johanna Tuomela
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  2. Jouko Sandholm
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  3. Peeter Karihtala
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  4. Joanna Ilvesaro
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  5. Katri S. Vuopala
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  6. Joonas H. Kauppila
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  7. Saila Kauppila
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  8. Dongquan Chen
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  9. Christine Pressey
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  10. Pirkko Härkönen
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  11. Kevin W. Harris
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  12. David Graves
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  13. Päivi K. Auvinen
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  14. Ylermi Soini
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  15. Arja Jukkola-Vuorinen
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  16. Katri S. Selander
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Corresponding author

Correspondence to Katri S. Selander.

Additional information

Johanna Tuomela, Jouko Sandholm, and Peeter Karihtala have equally contributed to this study.

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Tuomela, J., Sandholm, J., Karihtala, P. et al. Low TLR9 expression defines an aggressive subtype of triple-negative breast cancer. Breast Cancer Res Treat 135, 481–493 (2012). https://doi.org/10.1007/s10549-012-2181-7

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  • DOI: https://doi.org/10.1007/s10549-012-2181-7

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